An obesity model and corona multiomics analysis reveal high-density lipoprotein effects on lipid nanoparticle function

Lipid nanoparticles (LNPs) are currently of great interest for therapeutic nucleic acid delivery. Lipid-based nanoparticles are, however, difficult to study analytically and so our understanding of the interaction between LNPs and biological systems remains obscure, particularly in terms of biomolecular corona formation and the impact this has on therapeutic efficacy and targeting. Ideally, we would like to engineer particles to acquire corona components that facilitate targeting, cargo delivery and improved safety. This requires studying the relationship between LNPs, biofluids and the resulting coronas. The particle-corona complexes are, however, fragile and biofluids also contain particles (such as lipoproteins) with sizes and biochemical characteristics similar to lipid nanoparticles, so contamination with biological components is a challenge. Here we describe a rapid, automated, and unbiased isolation method for LNP biomolecular coronas, coupled with proteomic and lipidomic analysis. Using these analytical methods, we systematically studied, in lean and obese rats, the variation in LNP-mediated mRNA delivery caused by individual physiology. A comprehensive multivariate model links LNP corona content to efficacy, identifying and validating high-density lipoproteins as a previously unidentified factor affecting particle efficacy.